Extrahepatic deposition and cytotoxicity of lithocholic acid: studies in two hamster models of hepatic failure and in cultured human fibroblasts.
Effects of bile acids on tissues outside of the enterohepatic circulation may be of major pathophysiological significance under conditions of elevated serum bile acid concentrations, such as in hepatobiliary disease. Two hamster models of hepatic failure, namely functional hepatectomy (HepX), and 2-day bile duct ligation (BDL), as well as cultured human fibroblasts, were used to study the comparative tissue uptake, distribution, and cytotoxicity of lithocholic acid (LCA) in relation to various experimental conditions, such as binding of LCA to low-density lipoprotein (LDL) or albumin as protein carriers. Fifteen minutes after i.v. infusion of [24-(14)C]LCA, the majority of LCA in sham-operated control animals was recovered in liver, bile, and small intestine. After hepatectomy, a significant increase in LCA was found in blood, muscle, heart, brain, adrenals, and thymus. In bile duct-ligated animals, significantly more LCA was associated with blood and skin, and a greater than twofold increase in LCA was observed in the colon. In the hepatectomized model, the administration of LCA bound to LDL resulted in a significantly higher uptake in the kidneys and skin. The comparative time- and concentration-dependent uptake of [14C]LCA, [14C]chenodeoxycholic acid (CDCA), and [14C]cholic acid (CA) in cultured human fibroblasts was nonsaturable and remained a function of concentration. Initial rates of uptake were significantly increased by approximately tenfold, with decreasing hydroxylation of the respective bile acid. After 1 hour of exposure of fibroblasts to LCA, there was a significant, dose-dependent decrease in mitochondrial dehydrogenase activity from 18% to 34% of the control, at LCA concentrations ranging from 1 to 20 micromol/L. At a respective concentration of 100 and 700 micromol/L, CDCA caused a 35% and 99% inhibition of mitochondrial dehydrogenase activity. None of the bile acids tested, with the exception of 700 micromol/L CDCA, caused a significant release of cytosolic lactate dehydrogenase into the medium. In conclusion, we show that bile acids selectively accumulate in nonhepatic tissues under two conditions of impaired liver function. Furthermore, the extrahepatic tissue distribution of bile acids during cholestasis may be affected by serum lipoprotein composition. At a respective concentration of 1 and 100 micromol/L, LCA and CDCA induced mitochondrial damage in human fibroblasts, after just 1 hour of exposure. Therefore, enhanced extrahepatic uptake of hydrophobic bile acids during liver dysfunction, or disorders of lipoprotein metabolism, may have important implications for bile-acid induced cytotoxic effects in tissues of the systemic circulation.
Ceryak
S
S
Department of Medicine, The George Washington University Medical Center, Washington, DC 20037, USA.
Bouscarel
B
B
Malavolti
M
M
Fromm
H
H
D000410:Alanine Transaminase / Q000097:blood; D000469:Alkaline Phosphatase / Q000097:blood; D000818:Animals; D001652:Bile Ducts / Q000601:surgery; D001798:Blood Proteins / Q000737:chemistry; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002635:Chenodeoxycholic Acid / Q000378:metabolism / Q000633:toxicity; D019826:Cholic Acid; D002793:Cholic Acids / Q000378:metabolism / Q000633:toxicity; D006224:Cricetinae; D004764:Enterohepatic Circulation / Q000502:physiology; D005347:Fibroblasts / Q000378:metabolism; D006498:Hepatectomy; D006801:Humans; D007275:Injections, Intravenous; D008026:Ligation; D008077:Lipoproteins, LDL / Q000737:chemistry; D008095:Lithocholic Acid / Q000032:analysis / Q000493:pharmacokinetics* / Q000633:toxicity; D017093:Liver Failure / Q000503:physiopathology*; D008297:Male; D012709:Serum Albumin / Q000737:chemistry; D014018:Tissue Distribution
D001798:Blood Proteins; D002793:Cholic Acids; D008077:Lipoproteins, LDL; D012709:Serum Albumin; D002635:Chenodeoxycholic Acid; D008095:Lithocholic Acid; D000410:Alanine Transaminase; D000469:Alkaline Phosphatase; D019826:Cholic Acid